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Publication numberUS4522806 A
Publication typeGrant
Application numberUS 06/563,011
Publication dateJun 11, 1985
Filing dateDec 19, 1983
Priority dateOct 10, 1980
Fee statusLapsed
Also published asCA1168159A, CA1168159A1, DE3172144D1, EP0049830A2, EP0049830A3, EP0049830B1
Publication number06563011, 563011, US 4522806 A, US 4522806A, US-A-4522806, US4522806 A, US4522806A
InventorsHans R. Muhlemann, Ulrich P. Saxer
Original AssigneeLever Brothers Company
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Oral compositions for hexetidine and zinc salts for the synergistic inhibition of dental plaque
US 4522806 A
Oral compositions, such as mouthwashes, sprays, gels, oral foams, toothpastes and the like which include a combination of an antibacterial pyrimidine amine base, especially hexetidine, plus one or several zinc salts. This combination inhibits the formation of dental plaque synergistically, without staining the teeth.
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What is claimed:
1. An oral composition for inhibiting the formation of dental plaque comprising about 0.08 to about 3000 ppm w/w of hexetidine and zinc in cationic and cationizable form in a total quantity of about 4.0 to about 1265 ppm w/w.
2. The oral composition of claim 1 which comprises about 750 to about 3000 ppm w/w of hexetidine and zinc in cationic and cationizable form in a total quantity of about 215 to about 1265 ppm w/w.
3. The oral composition of claim 1 which further comprises a nonionic emulsifying agent.
4. The oral composition of claim 1 wherein the cationic and cationizable zinc is associated with anions selected from the group consisting of acetate, citrate, fluoride and mixtures thereof.
5. The oral composition of claim 1 in the form of a mouthwash.
6. The oral composition of claim 1 in the form of a spray.
7. The oral composition of claim 1 in the form of an oral foam.
8. The oral composition of claim 1 in the form of a lozenge.

This is a continuation application of Ser. No. 309,050, filed Oct. 6, 1981, now abandoned.


This invention relates generally to oral compositions and more particularly concerns a composition which inhibits the formation of dental plaque without staining the teeth.


The term "oral compositions" is used herein to designate products which in the ordinary course of usage are retained in the oral cavity for a time sufficient to contact substantially all of the dental and gingival surfaces, but which are not ingested. Such products include, for example, mouthwashes, sprays, dental gels, oral foams and dentifrices.

Dental plaque is a dense, tenacious deposit of oral bacteria. Calcification (mineralization) of dental plaque results in dental calculus. Calculus formation depends on the presence of plaque.

Plaque forms and grows on the surface of teeth, preferentially in the cervical, interdental and fissure areas and also on dental restorations, crowns, bridges and dentures. Plaque is the obligate cause of dental caries, and plaque and calculus are the causes of inflammatory destruction of the tooth-supporting gingival and periodontal structures (periodontitis).

A wide variety of chemical agents have been suggested to retard plaque formation and the resulting plaque diseases. Mechanical removal of plaque is attempted with oral hygiene measures, but average toothbrushing only partially results in plaque removal. Therefore, the additional use of chemical antibacterials inhibiting plaque formation in inaccessible dental areas is indicated. Germicides which have been proposed include phenolic compounds, halogenated bis-phenols (e.g. hexachlorophene), organic mercurials, hydroxyquinolines, iodine esters of hydroxybenzoic acids, chloramine T, and surface active compounds (detergents) among others. These germicides are excellent laboratory disinfectants but are relatively poor in vivo plaque inhibitors in contrast to cationic organic antibacterial agents, such as water soluble salts of cetylpyridinium, of quaternary ammonium bases (benzalkonium chloride), of alkylamines (fluoride of N,N,N'-tris-(2-hydroxyethyl)-N'-octadecyl-1,3-diaminopropane) and of cationic amidines, and water soluble salts of chlorhexidines, such as Hibitane, Alexidine and Vantocil.

The effect on plaque formation of mouthwashes used daily and containing cetylpyridinium chloride (Carter, H. G., Barnes, G. P.: Effects of three mouthwashes on existing dental plaque accumulations. J Prev Dent 2, 10, 1975; Ciancio, S. G., Mather, M. L., Bunnell, H. L.: Effect of a quaternary ammonium type mouthrinse on formed plaque. J Dent Res 54 A, Abstract 585, 1975), cetylpyridinium chloride plus a quaternary ammonium base (Domiphen bromide) (Barnes, G. P., Roberts, D. W., Katz, R. V., Woolridge, E. D.: Effects of two cetylpyridinium chloride-containing mouthwashes on bacterial plaque. J Periodontol 47, 419, 1976) or benzethonium chloride alone (Volpe, A. R., Kupczak, L. J., Brant, J. H., King, W. J., Kestenbaum, R. C., Schlissel, H. J.: Antimicrobial control of bacterial plaque and calculus and the effects of these agents on oral flora. J Dent Res 48, 832, 1969) is relatively modest when compared with amidines. This is evident when comparing mouthwashes containing chlorhexidine digluconate with other mouthwash antibacterials (Gjermo, P., Baastad, K. L., Rolla, G.: The plaque inhibiting capacity of 11 antibacterial compounds. J Peridont Res 5, 102, 1970; Muhlemann, H. R., Hulss, D., Steiner, E.: Antimicrobial rinses and proximal plaque on removable gold crowns. Helv Odont Acta 17, 89, 1973; and Bergenholtz, A., Hanstrom L.: The plaque-inhibiting effect of hexetidine (Oraldene®)-mouthwash compared to that of chlorhexidine. Community Dent Oral Epidemiol 2, 70, 1974.) Unfortunately, mouthrinsing with amidines will rapidly produce a cosmetically unacceptable brown stain on the teeth (Flotra, L., Gjermo, P., Rolla, G., Waerhaug, J.: Side effects of chlorhexidine mouthwashes. Scand J Dent Res 79, 119, 1971). Cationic detergents and amidines have also been found to irritate the oral mucosa even when used at recommended therapeutic concentrations in rinsing solutions (Flotra, L.: Different modes of chlorhexidine application and related local side effects. J Periodont Res 8, Supp. 12, 41, 1973).

The antiplaque properties of metal ions were mentioned as early as 1940 (Hanke, M. T.: Studies on the local factors in dental caries. I. Destruction of plaque and retardation of bacterial growth in the oral cavity. JADA 27, 379, 1940). U.S. Pat. No. 593,485 refers to zinc phenolsulfonate as bactericide. The use of zinc oxide or zinc phosphate for the stabilization of dental creams is described in U.S. Pat. No. 3,622,662. Zinc oxide and zinc sulphate are described in U.S. Pat. No. 3,624,199 for the same purpose. Effervescent antiplaque tablets containing zinc chloride are described in U.S. Pat. No. 3,888,976. Pader (U.S. Pat. No. 4,082,841) reported the anticalculus effect of zinc ions. A composition reducing the formation of dental calculus is reported in German Pat. No. 2,203,379.

Various zinc salts have been studied in clinical trials to determine their antiplaque potential when used in mouthwashes, but the results were conflicting. A zinc chloride solution at 1000 ppm zinc concentration was reported in one study to be effective (Skjorland, K., Gjermo, P., Rolla, G.: Effect of some polyvalent cations on plaque formation in vivo. Scand J Dent Res 86, 103, 1978), and in another trial to be totally ineffective (Compton, F. H., Beagrie, G. S.: Inhibitory effect of benzethonium and zinc chloride mouthrinses on human dental plaque and gingivitis. J Clin Periodontol 2, 33, 1975). Soluble zinc citrate displays a small plaque inhibitory action at zinc concentrations of 600 ppm (Addy, M., Richards, J., Williams, G.: Effects of a zinc citrate mouthwash on dental plaque and salivary bacteria. J Clin Periodontol 7, 309, 1980) and 1000 ppm (Waler, S. M., Rolla, G.: Plaque inhibiting effect of combinations of chlorhexidine and the metal ions zinc and tin. A preliminary report. Acta Odontol Scand 38, 201, 1980), respectively. Zinc chloride rinses (Zn=1000 ppm) clearly depresses calculus formation (Schmid, M. O., Schait, A., Muhlemann, H. R.: Effect of a zinc chloride mouthrinse on calculus deposits formed on foils. Helv Odont Acta 18, 22, 1974), and zinc chloride bound to carboxy-sulphate- and phosphate groups were reported to have deodorant properties. Zinc chloride complexed to polymers of carboxyl sulfate and phosphate groups prevents or controls mouth odor.

In recent years mechanisms of plaque inhibiting properties of metal ions have become increasingly evident (White, S. T., Taylor, P. P.: The effect of stannous fluoride on plaque scores. J Dent Res 58, 1850, 1979; Svatun, B., Gjermo, P., Eriksen, H. M., Rolla, G: A comparison of the plaque-inhibiting effect of stannous fluoride and chlorhexidine. Acta Odontol Scand 35, 247, 1977; Hock J., Tinanoff, N.: Resolution of gingivitis in dogs following topical applications of 0.4% stannous fluoride and toothbrushing. J Dent Res 58, 1652, 1979). Plaque apparently is only loosely adsorbed on the enamel in the presence of metal ions. Metal ions also interfere with the metabolic (enzymatic) activity of bacteria, particularly with acid formation from dietary carbohydrates. From among ions of silver, zinc, magnesium, tin and aluminum, stannous ions seem to possess the highest antiplaque activity (Svatun, B.: Plaque-inhibiting effect of dentifrices containing stannous fluoride. Acta Odontol Scand 36, 205, 1978; Gjermo, P., Rolla, G.: Plaque inhibition by antibacterial dentifrices. Scand J Dent Res 78, 464, 1970). Unfortunately, it is difficult to prevent hydrolysis and precipitate formation in mouthwashes containing water-soluble tin salts (Shannon, I. L. and Gibson, W. A.: Shelf life of aqueous solutions of stannous fluoride. USA School of Aerospace Medicine, Brooks Air Force Base, Texas, SAM-TDR-63-104). In addition, stannous fluoride is known to stain teeth. Yellowish discoloration is not known to occur with the use of zinc ions, such as zinc fluoride, zinc acetate and zinc chloride.

A mouthwash containing a 0.22% zinc chloride (Lavoris) has been marketed in the U.S. for many years. There is general agreement that zinc salts have a beneficial adstringent effect on inflamed oral mucosae and that they are modest plaque inhibitors.

Antiplaque and anticalculus effects have been claimed for zinc ions combined with tetradecylamine (U.S. Pat. No. 4,146,607), with glycine (British Patent Application GB No. 2,052,978 A), and with enzymes (U.S. Pat. No. 4,082,841). The combination of zinc salts with amidines (EPC Patent Application No. 0,026,252) is reported to prevent tooth discolorations without loss of amidine antiplaque action.

Antiplaque effects of oral rinses containing zinc salts and antibacterials have been reported in U.S. Pat. No. 4,022,880. The combination of zinc with antibacterials has been described in U.S. Pat. No. 4,022,880. Claims are only made for additive effects: "Our discovery concerns the co-action of zinc ions and an antibacterial agent, rather than a well defined synergistic property" ( column 4 of U.S. Pat. No. 4,022,880). The antibacterials listed in U.S. Pat. No. 4,022,880 are amidines, quaternary ammonium bases, phenolics a.s.o., but not pyrimidine amine bases nor hexetidine specifically. In addition many zinc salts are referred to, but not zinc fluoride. However, some scientific investigations have shown possible incompatibilities between solutions of zinc salts and quaternary ammonium bases. In another trial, zinc acetate combined with chlorhexidine digluconate was found to be slightly but not significantly superior in antiplaque action when compared with chlorhexidine alone (Waler, S. M., Rolla, G., supra).

Hexetidine, a saturated pyrimidine derivate, the analytical profile of which was recently reported, (Satzinger, G., Herrmann, W., Zimmermann, F.: Analytisches Profil des Rein-Hexetidins. Drug Research 25, 1849, 1975. (Godecke AG, Freiburg i.Br., West Germany)) has been used in mouthrinses for over 20 years. The chemical formula of Hexetidine is: ##STR1## 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5-pyrimidineamine.

Well known marketed mouthwashes containing 0.1 to 0.2 percent hexetidine are Drossadine, Hexoral, Hextril, Oraldene, Sterisol. They have been mainly recommended as pre- and postoperative astringent oral antiseptics and for the elimination of unpleasant breath.

Antiseptic oral effects of hexetidine, its depressive action on inflammed oral mucosae and its deodorant effects in the oral cavity were for the first time extensively reported in 1958 at a Symposium on Hexetidine, Northwestern University, Chicago, Ill. (Godecke Publication report on Hexoral®; Report of Warner-Chilcott on Hextril®).

The plaque inhibiting action of 0.1 percent hexetidine alone is similar to zinc salt solutions, is relatively moderate, and is more than 50 percent smaller than 0.2 percent chlorhexidine digluconate rinses (Muhlemann, H. R., Hulss, D., Steiner, E.: Antimicrobial rinses and proximal plaque on removable gold crowns. Helv Odont Act 17, 89, 1973; Muhlemann, H. R.: Auf dem Weg zum sauberen Zahn? SWISS DENT 2, No. 1-2, 7, 1981; Muhlemann, H. R., Saxer, U. P.: Plaque inhibition by rinsing solutions containing aminefluoride, hexetidine and zinc ions. Preprinted Abstract No. 17, ORCA-Congress 1981, Erfurt, DDR; Saxer, U. P., Muhlemann, H. R.: Plaque-inhibiting effect of zinc ions and fluoride, hexetidine and their combinations. Preprinted Abstract No. 18, ORCA-Congress 1981, Erfurt DDR). In addition, there are indications that retention of hexetidine in the oral cavity after rinsing, and subsequent antiglycolytic effects in plaque are less pronounced than in the case of chlorhexidine (Hefti, A., Widmer, B.: Reduktion des Keimpegels in der Mundhohle vor zahnarztlichen Behandlungen durch Mundwasser und Mundantiseptika. Schweiz Mschr Zahnheilk 90, 73, 1980) and amine chloride (Breitenmoser, Th.: The antiglycolytic action on dental plaque of amine chloride. Helv Odont Acta 19, 13, 1975), respectively.

Plaque and calculus reduction studies with combinations of zinc salts and a water-insoluble pyrimidine base hexitidine have hitherto not been described in theliterature.


It is an object of this invention to provide a novel oral antiplaque composition based on the combination of a water-insoluble pyrimidine base, hexetidine, plus one or several zinc salts and with a nonionic solubilizer (emulgator), and with optionally soluble fluoride salts.

The word "combination" is intended to mean either: the simultaneous use of the two agents zinc and hexetidine in one oral composition, such as a zinc-hexetidine toothpaste, or a mouthwash containing zinc plus hexetidine; or the immediate successive use of two different oral compositions, one containing hexetidine the other a zinc salt, as for example, the brushing of teeth with a toothpaste containing a zinc salt and the subsequent rinsing with a mouthwash containing hexetidine, or vice versa.

It has been discovered that zinc fluoride dissolved and emulgated at a physiological pH together with hexetidine in an alcohol containing aqueous mouthwash have a pronounced synergistic antiplaque action in animal caries tests, clinical experiments and microbiological media. Clinical plaque reduction is similar to or may exceed that produced by chlorhexidine, and without staining the teeth.

This invention encompasses novel oral compositions which contain hexetidine in combination with zinc salts and which are stable and which are used at a physiological oral pH. The combination of hexetidine with zinc salts results in a highly synergistic statistically significant inhibition of oral microorganisms and of plaque formation on teeth and dental restorations which improves oral hygiene and simultaneously depresses the inflammation of gums (gingivitis). The use of the zinc-hexetidine-combination at eight hour intervals almost totally inhibits growth of plaque without irritating the oral mucosae and without staining the teeth.

The antibacterial effect of the zinc-hexetidine-combination is specific. Replacement of zinc by other metal ions or replacement of hexetidine by amidines, quaternary ammonium bases a.s.o. will annihilate the antibacterial synergism of the zinc-hexetidine-combination at low concentrations.

Preferably the composition according to this invention contains one of the following combinations: hexetidine and zinc fluoride, or hexetidine, zinc fluoride plus other zinc salts, or hexetidine plus zinc fluoride and other zinc salts, or hexetidine and non-fluoride zinc salts. Also, a water-insoluble pyrimidine amine base preferably is rendered soluble and is emulgated at a physiological pH, preferably in a nonionic emulgator (Cremophor) and ethanol. The antiplaque zinc-hexetidine-combination is preferably used with both agents included in one oral composition. Alternatively, the two agents each may be in a separate composition and used successively one after the other.

These and other objects of the invention will become apparent from a further and more detailed description of the invention to follow.


Experimental evaluation was made of the inhibition of plaque formation in (a) animal experiments; (b) clinical investigations; and (c) microbiological media.

(a) Animal Experimentation

Four groups of 13 twenty one day old Osborne-Mendel rats each were inoculated orally with a suspension of Streptococcus mutans OMZ 176 and Actinomyces viscosus Ny 1. Subsequently the cariogenic sucrose containing diet 2000 a was offered ad libitum for 3 weeks. The solutions specified in Table I were applied to the rat molars 3 times per day. At the end of the experiment the extent of plaque formed on the molars was evaluated with a scoring system. The findings are summarized in Table I.

              TABLE I______________________________________The effects on plaque formation of various solutions containingzinc ions and hexetidine in Osborne-Mendel rats fed thecariogenic diet 2000 a                      Average extent of                      plaque formed onTopically applied           Abbreviated                      molars+,compounds       designation                      PU______________________________________A   250 ppm F as NaF               H2 O Control  3.5B   250 ppm F as NaF               Hex 750 ppm        3.4     *    750 ppm F. Hexetidine      *               *C   250 ppm F from ZnF2               Zinc 75 ppm                          *       2.2    750 ppm Zn from ZnF2    + Zinc acetate                             *D   250 ppm F from ZnF2               Hex 750 ppm        1.1    750 ppm Zn from ZnF2               +    + Zinc acetate  Zinc 750 ppm    750 ppm Hexetidine______________________________________ + theoretical maximum value = 4.0 *PF significances

Inhibition (1.1 PU) of plaque formation was synergistic and significantly greatest in the case where zinc fluoride/zinc acetate plus hexetidine were combined in one solution (treatment D). Hexetidine alone was without effect (3.4 PU) and zinc fluoride was inhibitory (2.2 PU).

(b) Clinical Investigations

Six female dental hygiene students who ranged in age from 20 to 26 years old, and who were known from previous investigations to be heavy plaque formers when consuming sucrose candies frequently, participated in a clinical test of four mouthwash solutions. Prior to each of the four consecutive 7-day-rinsing periods, the subjects had their teeth cleaned, pumiced and polished professionally. The volunteers then were randomly assigned to one of the 4 anti-plaque rinsing treatments listed below. For ethical considerations a neutral water control rinse was omitted. The subjects had to rinse 3 times a day (twice under supervision) for 30 seconds and had to refrain from tooth brushing and other mechanical hygiene procedures.

The four rinsing treatments utilized are as follows: (1) a solution containing 0.1 percent chlorhexidine digluconate freshly prepared from Plak Out Liquid. Plak Out Liquid is a 10 percent chlorhexidine concentrate (HAWE, Gentilino-Lugano, Switzerland), and 4 drops in 10 ml of water provides a 0.1% solution; (2) a solution containing 0.1 percent hexetidine plus zinc fluoride (ZnF2) at 215 ppm zinc and 250 ppm fluorine (adapted with sodium fluoride) concentrations; (3) a solution containing N,N,N'-tris-(2-hydroxyethyl)-N'-octadecyl-1,3-diaminopropane dihydrofluoride (amine fluoride, compound 297) at 250 ppm fluorine plus zinc fluoride (ZnF2) at 215 ppm zinc; and (4) a solution containing amine fluoride 297 (250 ppm fluorine) plus stannous fluoride (SnF2) at 250 ppm fluorine.

Lycasin 8055 (Roquette Freres, Lestrem, France) was added to all treatments. It is a sweetening agent containing mainly maltitol, sorbitol and hydrogenated dextrines. Each object rinsed with one of the four experimental solutions which was assigned at random. There were no set time intervals between the treatments. The study was performed double blind. The rate of plaque formation was documented at the end of each experimental period by standardized color photographs of the teeth stained with Displac. The extent of plaque formation was determined planimetrically using projected Kodachrome slides. The findings are summarized in Table II.

              TABLE II______________________________________The effect of four different mouthwash solutions, one con-taining chlorhexidine, another hexetidine and zinc fluoride(ZnF2), another amine fluoride 297* and ZnF2, and anotheramine fluoride 297 and SnF2, on plaque formation in 6 subjectsabstaining from mechanical oral hygiene measures during 4consecutive 7 day rinsing periods. Averages of planimetricunits PU ± standard deviation.     Positive             Amine  Amine     control              Fluoride                                 FluorideRinsing   chlorhexi-               Hexetidine 297* + 297* +Solution  dine      ZnF2  ZnF2                                 + SnF2______________________________________7-day extent     188 ± 90               30 ± 9  101 ± 54                                 61 ± 22ofpaquel,PUTheoretical     26.9      4.3        14.4   8.7amount ofplaque formedper day______________________________________ *N,N,N'--tris(2-hydroxyethyl)-N'--octadecyl1,3-diaminopropane.2HF

Inhibition of plaque formation with the hexetidine-ZnF2 combination was significantly superior to the chlorhexidine rinse (Pt <0.01), and to the rinses containing amine fluoride+SnF2 (Pt <0.05) and amine fluoride+ZnF2 (Pt <0.05). When rinsing with 0.1 percent chlorhexidine, plaque at an average of 26.9 PU per day was formed (Table II). The same volunteers who in a previous and similar investigation rinsed with water containing Lycasin 8055 had produced plaque at an average of 50.2 PU per day, suggesting, therefore, the relatively strong antiplaque activity of the 0.1 percent chlorhexidine rinse (Plak Out) in the present study (26.9 PU/day). No staining of teeth resulted from the treatment with hexetidine+ZnF2. A yellowish stain, however, was produced by the chlorhexidine rinse. All of the rinsing solutions showed stability and remained clear over the treatment periods and for several months thereafter.

In a second clinical test with 10 dental hygiene students, the antiplaque effects of zinc fluoride, hexetidine, and ZnF2 plus hexetidine were tested. The rinsing solutions were: (1) control (NaF, 250 ppm fluorine); (2) ZnF2 (250 ppm fluorine, 750 ppm zinc); (3) Hexetidine (750 ppm) plus NaF (250 ppm); and (4) ZnF2 (250 ppm fluorine, 750 ppm zinc) plus hexetidine (750 ppm) pH 5.9. The solutions were combined with aromatics. They were well tasting and non-irritative to oral mucosae. The experimental procedures were similar to those reported for the previous experiment. At the beginning of the four one-week-rinsing periods, the 10 female dental hygiene students were given a professional tooth cleaning. They then refrained from mechanical oral hygiene procedures and rinsed 3 times per day (twice under supervision) with 10 ml for 30 sec. The test solutions were assigned at random. The plaque reductions observed in the double blind study are summarized in Table III.

              TABLE III______________________________________Average plaque indices ± standard deviation and averageplanimetric units in 10 volunteers refraining from toothbrushing and other mechanical oral hygiene procedures butrinsing during four one-week test periods with one of fourhexetidine-and zinc fluoride solution.                Percentage of       Pl I     vestibular tooth       Plaque Index                surfaces covered       (Silness-Loe)                with plaque (PU)______________________________________Control       2.58 ± 0.28                    33.4 ± 16.57ZnF2     2.16 ± 0.38                    23.2 ± 14.44Hexetidine    2.11 ± 0.72                    17.4 ± 8.07Zn + Hexetidine         0.77 ± 0.55                    3.5 ± 2.17______________________________________

The results show the synergistic and highly significant plaque inhibition by the zinc-hexetidine-mouthwash.

(c) Microbiological Investigation

The synergistic antibacterial effect of the zinc hexetidine-combination is clearly evident in microbiological investigations. Twenty-four hour growth and acid production of Streptococcus mutans cultured in a glucose-containing synthetic FMC-broth are totally inhibited by zinc acetate alone at a minimal concentration of 40 ppm zinc, and by hexetidine alone at 0.4 ppm. The combination of both agents in the broth results in total bacterial inhibition at a concentration of 4.0 ppm zinc and 0.08 ppm hexetidine. Zinc or hexetidine are without antibacterial effects at these low concentrations.

The synergistic antibacterial effect can also be observed if zinc and hexetidine, are used sequentially on washed streptococcal cultures, either the zinc being applied first and subsequentally hexetidine being applied, or the hexetidine being applied first and then the zinc being applied. The synergistic inhibition of plaque microorganisms with the zinc-hexetidine-combination is specific. Other metal ions, as for example, stannous ions, combined with hexetidine, or other antibacterials combined with zinc only cause additive antibacterial effects.

In summary, the synergistic and specific antiplaque effect of the disclosed zinc hexetidine combination has been demonstrated in a rat caries test and in two independent clinical plaque studies, using organoleptically acceptable mouth rinses. Synergistic inhibition was also observed in microbiological laboratory investigations. Oral compositions with derivates of pyrimidine amine bases or of hexetidine plus zinc salts dissolved in the emulgator Cremophor are included in the present invention.

Components of exemplary oral compositions in accordance with the present invention are given in the following examples:

EXAMPLE I Mouthwash

______________________________________Hexetidine                   0.1Zinc fluoride                0.1Sodium fluoride              0.05Glycerol                     5.0Cremophor EL                 0.25Ethanol                      10.0Polyoxyethylen-sorbitanmonoleate                        0.1Aromatics, saccharin         0.15Water                  ad    100.0______________________________________
EXAMPLE II Mouthwash

______________________________________Hexetidine                0.2Zinc citrate              0.15Glycerol                  5.0Cremophor EL              0.25Ethanol                   10.0Aromatics, saccharin      0.1Water               ad    100.0______________________________________

______________________________________Hexetidine                0.2Zinc acetate              0.1Potassium fluoride        0.05Cremophor EL              0.5Ethanol                   15.0Aromatics, saccharin      0.2Water               ad    100.0Propellant______________________________________

______________________________________Hexetidine                0.2Hydroxyethylcellulose     3.0Zinc fluoride             0.2Sodium fluoride           2.1Negion                    0.5Cremophor EL              1.0Flavor, coloring agents   0.5Water               ad    100.0______________________________________
EXAMPLE V Clear Dental Gel

______________________________________Hexetidine                0.1Zinc acetate              0.1Sodium fluoride           0.2Sorbitol (70% solution)   50.0Glycerol                  27.0Aerosil D 200             5.0Sident 3                  15.0Cremophor EL              0.3Sweetener, color, flavor  2.0Water               ad    100.0______________________________________
EXAMPLE VI Toothpaste

______________________________________Hexetidine               0.3Zinc fluoride            0.1Sodium fluoride          0.1Guar gum                 1.5Syloid                   12.5Aerosil                  2.0Glycerol                 30.0Cremophor EL             0.5Aromatics                1.5Water              ad    100.0______________________________________

______________________________________Hexetidine               0.001Zinc fluoride            0.003CMC                      0.1Silica             ad    1.0______________________________________

Zinc and hexetidine can also be combined using two different oral compositions, as for example, toothbrushing with a toothpaste of Example VI, which does not contain zinc and then subsequently rinsing with a mouthwash of Example I which does not contain hexetidine.

The names Hibitane, Alexidine, Vantocil, Domiphen bromide, Lavoris, Drossadine, Hexoral, Hextril, Oraldene, Sterisol, Lycasin, Cremophor, Plak Out and Displac are trademarks.

In view of the above description, it is likely that modifications and improvements will occur to those skilled in the art which are within the scope of this invention and which is defined solely in the following claims.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3095356 *Feb 20, 1956Jun 25, 1963Monsanto ChemicalsDentifrice comprising insoluble sodium metaphosphate and a cadmium, tin, zinc, manganese or iron compound to inhibit calcium ion sequestering
US3622662 *Apr 21, 1969Nov 23, 1971Colgate Palmolive CoStable dental cream
US3985537 *Aug 7, 1974Oct 12, 1976Kali-Chemie AktiengesellschaftProcess for making calcined alkali phosphates of high citrate solubility for use as fertilizers
US3989814 *Mar 17, 1975Nov 2, 1976Colgate-Palmolive CompanyCalcium pyrophosphate abrasive system for dentifrice
US4022880 *Aug 11, 1975May 10, 1977Lever Brothers CompanyAnticalculus composition
US4100269 *May 6, 1977Jul 11, 1978Lever Brothers CompanyAnticalculus dentifrice
US4138477 *May 28, 1976Feb 6, 1979Colgate Palmolive CompanyComposition to control mouth odor
US4141968 *Nov 3, 1976Feb 27, 1979Doll GmbhNovel salts of 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine in compositions having bacteriostatic activity
US4142050 *Nov 3, 1976Feb 27, 1979Doll GmbhSalts of 1,3-bis(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine
US4170634 *Jan 17, 1977Oct 9, 1979Colgate Palmolive CompanyModified abrasive system for dentifrices
US4187288 *Oct 4, 1978Feb 5, 1980Colgate Palmolive CompanyModified abrasive system for dentifrices
GB771768A * Title not available
GB1284544A * Title not available
GB1284545A * Title not available
GB1284546A * Title not available
GB1310374A * Title not available
GB1461896A * Title not available
GB1533634A * Title not available
GB2001526A * Title not available
GB2084870A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4647452 *Nov 8, 1985Mar 3, 1987Lever Brothers CompanyOral compositions of salicylamides and zinc salts for the synergistic inhibition of dental plaque
US4656031 *May 7, 1985Apr 7, 1987Lever Brothers CompanyDentifrice compositions
US4666517 *Jun 4, 1986May 19, 1987Colgate-Palmolive Co.Antiplaque oral composition
US4770634 *Jun 11, 1986Sep 13, 1988Pellico Michael AMethod for treating teeth with foamable fluoride compositions
US4774078 *Oct 6, 1986Sep 27, 1988Colgate-Palmolive CompanyStable antiplaque dentifrice based on hexetidine, zinc ion and fluoride
US4961923 *Oct 2, 1989Oct 9, 1990Dentsply Management Corp.Irrigants for use in scaling and/or lavage apparatus
US4992276 *Dec 14, 1988Feb 12, 1991Warner-Lambert CompanyAntiseptic compositions containing hexahydro-5-pyrimidinamine compounds and thymol and methods for preparing same
US5096702 *Sep 11, 1990Mar 17, 1992Chesebrough-Pond's Usa Co., Division Of Conopco, Inc.Dentifrice compositions
US5104644 *Oct 25, 1990Apr 14, 19927-L CorporationMouthrinse composition
US5145666 *Oct 23, 1991Sep 8, 1992The Proctor & Gamble Co.Methods of reducing plaque and gingivitis with reduced staining
US5174990 *Sep 5, 1991Dec 29, 19927-L CorporationMouthrinse and method of preparation
US5213790 *Oct 23, 1991May 25, 1993The Procter & Gamble Co.Methods of reducing plaque and gingivitis with reduced staining
US5240696 *Aug 5, 1992Aug 31, 1993Chesebrough-Pond's Usa Co., Division Of Conopco, Inc.Treatment of periodontitis
US5281410 *Jun 15, 1992Jan 25, 1994The Proctor & Gamble CompanyMethods of reducing plaque and gingivitis with reduced staining
US5281411 *Jul 31, 1992Jan 25, 1994The Procter & Gamble CompanyOral compositions
US5292527 *Jul 2, 1992Mar 8, 1994Bausch & Lomb IncorporatedNon-alcoholic aqueous mouthwash
US5310546 *Dec 24, 1992May 10, 19947-L CorporationMouthrinse and method of preparation
US5328690 *Feb 21, 1991Jul 12, 1994University Of South AlabamaPolyamino acid dispersants
US5330748 *May 19, 1993Jul 19, 1994Church & Dwight Co., Inc.Dentifrices containing zinc oxide particles
US5385727 *May 19, 1993Jan 31, 1995Church & Dwight Co., Inc.Dentifrices containing zinc oxide particles and sodium bicarbonate
US5455024 *Jan 26, 1995Oct 3, 1995Church & Dwight Co., Inc.Dentifrices containing zinc oxide particles and sodium bicarbonate
US5514366 *May 30, 1995May 7, 1996Diamond; Jeffrey H.Dental and oral preparation for smokers for solubilizing and removing tobacco tars as well as onion and garlic essential oils
US5587147 *Jun 30, 1994Dec 24, 1996Church & Dwight Co., Inc.Aqueous zinc-polyamide complex solution
US5662888 *May 3, 1996Sep 2, 1997Jeffrey Mitchell LaboratoriesToothpaste for smokers for solubilizing and removing tobacco tars
US5714447 *Jan 24, 1996Feb 3, 1998Church & Dwight Co., Inc.Deodorant soap or detergent composition containing a zinc compound and a polyamine
US5824289 *Mar 5, 1996Oct 20, 1998Sultan Dental ProductsDental fluoride foam
US5851512 *May 30, 1997Dec 22, 1998Ultradent Products, Inc.Dental compositions having a sticky matrix material for treating sensitive teeth
US5855870 *May 30, 1997Jan 5, 1999Ultradent Products, Inc.Method for treating sensitive teeth
US5948390 *Aug 18, 1998Sep 7, 1999Pfizer Inc.Stable zinc/citrate/CPC oral rinse formulations
US5985249 *Oct 14, 1997Nov 16, 1999Ultradent Products, Inc.Sticky dental compositions for adhering a passive-type dental tray over a person's teeth
US6030212 *Sep 27, 1996Feb 29, 2000Dentsply Research & Development Corp.Stacking reservoir and scaler system
US6036943 *Oct 14, 1997Mar 14, 2000Ultradent Products, Inc.Methods for treating a person's teeth using sticky dental compositions in combination with passive-type dental trays
US6086372 *Jun 4, 1997Jul 11, 2000Block Drug Company, Inc.Dental and oral preparation
US6086856 *Sep 19, 1995Jul 11, 2000Oralcare Systems, Inc.System for delivering foamed oral hygiene compositions
US6190642Oct 18, 1994Feb 20, 2001Dentsply Research & Development Corp.Irrigating and lavage compositions
US6251369Oct 19, 1998Jun 26, 2001Sultan Dental ProductsDental fluoride foam
US6293793Sep 29, 1999Sep 25, 2001Dentsply Research & Development Corp.Stackable reservoir and scaler system
US6306370Nov 12, 1998Oct 23, 2001Ultradent Products, Inc.Compositions and methods for whitening and desensitizing teeth
US6306372 *Jun 21, 2000Oct 23, 2001Noville Inc.Oral hygiene compositions which mask the burn sensation and the astringency of eucalyptol and zinc
US6309625Nov 12, 1998Oct 30, 2001Ultradent Products, Inc.One-part dental compositions and methods for bleaching and desensitizing teeth
US6344184Jul 13, 2000Feb 5, 2002Orix AsOral composition for inhibiting oral malodor
US6368576Oct 23, 2000Apr 9, 2002Ultradent Products, Inc.Methods for bleaching, opacifying and desensitizing teeth
US6551579May 29, 2001Apr 22, 2003The Procter & Gamble CompanyDelivery systems for a tooth whitener
US6582708Jun 28, 2000Jun 24, 2003The Procter & Gamble CompanyTooth whitening substance
US6884426Dec 17, 2002Apr 26, 2005The Procter & Gamble Co.Methods for whitening teeth
US6924325Jun 21, 2002Aug 2, 2005Kerr CorporationSilver-containing dental composition
US6949240May 23, 2002Sep 27, 2005The Procter & Gamble CompanyTooth whitening products
US7018622Oct 24, 2002Mar 28, 2006The Procter & Gamble CompanyStructures and compositions increasing the stability of peroxide actives
US7122199Apr 6, 2005Oct 17, 2006The Procter & Gamble CompanyMethods for whitening teeth
US7300645Oct 24, 2002Nov 27, 2007Sunstar Kabushiki KaishaOral composition comprising isomalt and remineralizing enhancing agent
US7687650Mar 30, 2010Jr Chem, LlcChemical compositions and methods of making them
US7867522Dec 29, 2006Jan 11, 2011Jr Chem, LlcMethod of wound/burn healing using copper-zinc compositions
US7897800Mar 1, 2011Jr Chem, LlcChemical compositions and methods of making them
US7927614Jun 14, 2006Apr 19, 2011Jr Chem, LlcAnti-aging treatment using copper and zinc compositions
US8148563Feb 19, 2010Apr 3, 2012Jr Chem, LlcChemical compositions and methods of making them
US8178582May 15, 2012Alcon Research, Ltd.Pharmaceutical compositions having desirable bioavailability
US8246999Aug 21, 2012Iowa State University Research Foundation, Inc.Capped mesoporous silicates
US8268299Sep 20, 2007Sep 18, 2012Alcon Research, Ltd.Self preserved aqueous pharmaceutical compositions
US8273791Dec 10, 2008Sep 25, 2012Jr Chem, LlcCompositions, kits and regimens for the treatment of skin, especially décolletage
US8323630Dec 4, 2012Alcon Research, Ltd.Self-preserved aqueous pharmaceutical compositions
US8388941Sep 20, 2007Mar 5, 2013Alcon Research, Ltd.Self preserved aqueous pharmaceutical compositions
US8505730Aug 23, 2012Aug 13, 2013Jr Chem, LlcCompositions, kits and regimens for the treatment of skin, especially décolletage
US8647644Apr 19, 2007Feb 11, 2014Iowa State University Research Foundation, Inc.Methods of using capped mesoporous silicates
US8722735Oct 4, 2011May 13, 2014Alcon Research, Ltd.Pharmaceutical compositions having desirable bioavailability
US8754123Apr 9, 2012Jun 17, 2014Alcon Research, Ltd.Pharmaceutical compositions having desirable bioavailability
US8778311Mar 20, 2007Jul 15, 2014The Procter & Gamble CompanyOral zinc compositions
US8936778Apr 10, 2007Jan 20, 2015Ultradent Products, Inc.Methods for bleaching and desensitizing teeth
US8952057Jun 16, 2011Feb 10, 2015Jr Chem, LlcCompositions for anorectal use and methods for treating anorectal disorders
US9044484Jun 17, 2010Jun 2, 2015Alcon Research, Ltd.Aqueous pharmaceutical compositions containing borate-polyol complexes
US9144561May 1, 2014Sep 29, 2015Alcon Research, Ltd.Pharmaceutical compositions having desirable bioavailability
US9421265Apr 20, 2015Aug 23, 2016Alcon Research, Ltd.Aqueous pharmaceutical compositions containing borate-polyol complexes
US20030059381 *Oct 24, 2002Mar 27, 2003Goodhart Lesle MarieStructures and compositions increasing the stability of peroxide actives
US20030068284 *Dec 17, 2002Apr 10, 2003The Procter & Gamble CompanyMethods for whitening teeth
US20030219389 *May 23, 2002Nov 27, 2003The Procter & Gamble CompanyTooth whitening products
US20040002557 *Jun 21, 2002Jan 1, 2004Xuejun QianSilver-containing dental composition
US20050136082 *Oct 15, 2004Jun 23, 2005Cosmetica, Inc.Polymeric odor absorption ingredients for personal care products
US20050196352 *Apr 6, 2005Sep 8, 2005The Procter & Gamble CompanyMethods for whitening teeth
US20050249680 *Jul 14, 2005Nov 10, 2005Goodhart Lesle MStructures and compositions increasing the stability of peroxide actives
US20050265931 *Jun 24, 2005Dec 1, 2005Kerr CorporationSilver-containing dental composition
US20050287086 *Aug 9, 2005Dec 29, 2005The Procter & Gamble CompanyTooth whitening products
US20060018966 *Sep 20, 2004Jan 26, 2006Lin Victor SAntimicrobial mesoporous silica nanoparticles
US20060254988 *May 10, 2005Nov 16, 2006Confirm Monitoring Systems, Inc.Methods and compositions for the treatment of water
US20070196287 *Apr 10, 2007Aug 23, 2007Ultradent Products, Inc.Methods for bleaching and desensitizing teeth
US20070224134 *Mar 20, 2007Sep 27, 2007The Procter & Gamble CompanyOral zinc compositions
US20070269471 *Jul 31, 2007Nov 22, 2007The Procter & Gamble CompanyMethods of tooth bleaching
US20080025927 *Jul 31, 2007Jan 31, 2008Sagel Paul ADelivery system for an oral care substance
US20080075790 *Sep 20, 2007Mar 27, 2008Alcon Manufacturing, Ltd.Self preserved aqueous pharmaceutical compositions
US20090232763 *Mar 3, 2009Sep 17, 2009Kabra Bhagwati PAqueous pharmaceutical compositions containing borate-polyol complexes
US20090234004 *Mar 13, 2009Sep 17, 2009Kabra Bhagwati PPharmaceutical compositions having desirable bioavailability
US20090234013 *Mar 13, 2009Sep 17, 2009Kabra Bhagwati PPharmaceutical compositions having desirable bioavailability
US20100021561 *Sep 20, 2007Jan 28, 2010Chowhan Masood ASelf-preserved aqueous pharmaceutical compositions
US20100021562 *Sep 20, 2007Jan 28, 2010Chowhan Masood ASelf preserved aqueous pharmaceutical compositions
US20100324031 *Jun 17, 2010Dec 23, 2010Kabra Bhagwati PAqueous pharmaceutical compositions containing borate-polyol complexes
US20110195132 *Aug 11, 2011Alcon Research, Ltd.Self-Preserved Aqueous Pharmaceutical Compositions
USRE42126Jun 30, 2000Feb 8, 2011The Procter & Gamble CompanyDelivery system for oral care compositions comprising organosiloxane resins using a removable backing strip
DE202009019087U1Mar 13, 2009May 20, 2016Alcon Research, Ltd.Pharmazeutische Zusammensetzungen mit wünschenswerter Bioverfügbarkeit
EP2599475A2Mar 13, 2009Jun 5, 2013Alcon Research, Ltd.Pharmaceutical composition having desirable bioavailability
EP2705836A1Mar 13, 2009Mar 12, 2014Alcon Research, Ltd.Pharmaceutical compositions having desirable bioavailability
EP3042646A1Mar 13, 2009Jul 13, 2016Alcon Research, Ltd.Pharmaceutical compositions having desirable bioavailability
WO2009117316A2Mar 13, 2009Sep 24, 2009Alcon Research, Ltd.Pharmaceutical compositions having desirable bioavailability
U.S. Classification424/52, 424/642, 424/54
International ClassificationA61P1/02, A61K8/00, A61K8/27, A61K33/30, A61K, C07D, A61K8/49, A61Q11/00, A61K8/21, C01G
Cooperative ClassificationA61Q11/00, A61K8/27, A61K8/4953
European ClassificationA61K8/27, A61Q11/00, A61K8/49F2
Legal Events
May 12, 1988ASAssignment
Effective date: 19880101
Effective date: 19880101
Aug 26, 1988FPAYFee payment
Year of fee payment: 4
Jun 26, 1992FPAYFee payment
Year of fee payment: 8
Jan 12, 1993REMIMaintenance fee reminder mailed
Jan 14, 1997REMIMaintenance fee reminder mailed
Jun 8, 1997LAPSLapse for failure to pay maintenance fees
Aug 19, 1997FPExpired due to failure to pay maintenance fee
Effective date: 19970611